The objective of this proposal is to understand the mechanisms that are responsible for marrow graft rejection in the mouse. Previous studies had shown that the acute rejection of allogeneic marrow grafts is due to natural killer cells which acquire in vivo specificity by making use of antibody that induces them to reject marrow. Since this mechanism does not explain all known phenomena in marrow graft rejection it is the objective of this proposal to uncover the not yet discovered mechanisms that play a role in marrow graft rejection. The first aim of this proposal is to characterize the cell surface phenotype of a new type of cell that we have identified to be responsible for acute rejection of allogeneic marrow grafts. We will use an adoptive transfer assay from responder to nonresponder mice in combination with antibody treatment to identify this cells. The second aim is to understand the relationship of acute and delayed graft rejection in an attempt to find out whether both mechanisms share the same specificities and effector cells. Using in vitro cytotoxicity assays and in vivo competition assays attempts will be made to determine the fine specificity of the effector cells responsible for acute and delayed rejection. In approaches very similar to those used to characterize the cells responsible for allogeneic marrow graft rejection we will investigate and try to isolate the cell responsible for hybrid resistance. Cell lines of both types of cells will be established and attempts will be made to clone these cells in lymphokine containing media. We will study the mode of action of these cells in both in vivo and in vitro assays. Biochemical procedures will be used to explore whether these cells express T cell receptors and if not attempts will be made to find out what the nature of their receptors may be. Since the hybrid resistance effector mechanism appears to express autoreactive potential we will test the hypothesis that the hybrid resistance cell is involved in the induction of autoimmunity. To do this F1 hybrid mice will be transplanted with marrow to stimulate the hybrid resistance effector mechanism and the production of autoantibody will be assessed.